Clarithromycin is the USAN generic name of the 6-O-methylerythromycin A (formula I). It is a compound derived from erythromycin A which, like this, belongs to the macrolide antibiotics group. The structural difference between both compounds lies in the methylation of the hydroxyl at position 6 of the macrolactone. This modification avoids the inactivation that the erythromycin A undergoes due to the gastric acids and the subsequent reduction in absorption (Nakagawa, Y., Itai, S., Yoshida, T., Nagai, T., Chem. Pharm. Bull., 1992, 40, 725-728). 
This compound was first disclosed by Y. Watanabe et al. (Taisho Pharmaceutical Co.) in the patent document EP 41.355 (and in the equivalent document U.S. Pat. No. 4,331,803). The process disclosed in said document starts from N-de-methylerythromycin A and protects the 2xe2x80x2-hydroxyl and the de-methylamine group in the form of a benzyloxycarbonyl derivative. Next, the 6-hydroxyl is methylated with methyl iodide and the 2xe2x80x2-hydroxyl and the de-methylamine group becomes unprotected by hydrogenolysis. Finally, the amine group is methylated with formaldehyde in a reductive methylation.
Since the publication of said patent document other alternative methods have been developed to obtain clarithromycin starting from erythromycin A. The common characteristic of said methods is to previously obtain the erythromycin A 9-oxime, which is protected together with the 2xe2x80x2-hydroxyl to subsequently proceed with the 6-hydroxyl methylation. These processes end with the unprotection of the oxime and the 2xe2x80x2-hydroxyl followed by the elimination of the oxime group by means of a NaHSO3 treatment. Said alternative methods differ in the protective group used to block the oxime group and the 2xe2x80x2-hydroxyl. Thus, alkoxy-carbonyl (EP 158.467) and benzyl or substituted benzyl groups (EP 195.960) have been used to protect both groups. A benzyl or substituted benzyl group and the 2xe2x80x2-hydroxyl have also blocked the oxime with a benzyloxycarbonyl group (EP 180.415) or with a trimethylsilyl group (EP 260.938).
Subsequently, the use of a mixed acetal to protect the oxime group has been disclosed (U.S. Pat. No. 4,990,602), followed by the protection of the 2xe2x80x2-hydroxyl and 4xe2x80x3-hydroxyl groups using trimethylsilylated derivatives and the 6-hydroxyl methylation with methyl iodide. The subsequent unprotection of the silyl groups and the acetal by means of a treatment with formic acid and elimination of the oxime group with Na2S2O5 would permit obtaining the clarithromycin, although said stages are not disclosed in said patent document U.S. Pat. No. 4,990,602.
In an example of said patent document U.S. Pat. No. 4,990,602, one starts with the erythromycin A oxime, which is treated in a methylene chloride solution with the diisopropyl acetal of the ciclohexanone in the presence of pyridine hydrochloride to obtain the mixed acetal of said oxime. Next, the 2xe2x80x2-hydroxyl and 4xe2x80x3-hydroxyl groups are protected by means of a treatment with trimethylsilylmidazole and chlortrimethylsilane in methylene chloride and finally the 6-hydroxyl group is methylated with methyl iodide and potassium hydroxide in a 1:1 mixture of dimethyl-sulfoxide and tetrahydrofuran to obtain the erythromycin A 2xe2x80x2,4xe2x80x3-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxy-cyclohexyl] oxime, which is transformed into the clarithromycin as noted above.
The object of the present invention is a new process that permits clarithromycin synthesis in a simple manner and with a high yield characterized by:
Starting from the erythromycin A oxime hydrochloride, which is transformed into clarithromycin by means of a synthetic sequence which in its first three stages avoids having to isolate the intermediate products, which facilitates its industrial applicability.
Simplification of the number of solvents used in the first three stages of the synthesis.
The use of catalytic amounts ( less than 1% in weight) of pyridine salt in the synthesis reaction of the mixed acetal of the oxime.
All the clarithromycin synthesis processes that achieve acceptable yields start from the erythromycin A 9-oxime. In the known 9-oxime synthesis procedures (see documents GB 110.0504, EP 342.990), it is passed through a salt, that can be isolated or not, before obtaining the oxime. During the investigation it has been found that the use of the erythromycin A 9-oxime hydrochloride permits advantageously performing the clarithromycin synthesis when, in its first synthesis stage, the oxime group is protected by a 1,1-diisopropoxycyclohexane to form a mixed acetal.
It has been found that the use of the erythromycin A 9-oxime hydrochloride permits, surprisingly, reducing, to a great extent, the amount of acid catalyst needed to perform the protection reaction of the hydroxyl group of the oxime.
The process, according to the invention, starts with the use of the erythromycin A 9-oxime hydrochloride, which is made to react with the diisopropylic acetal of the cyclohexanone, using methylene chloride as a solvent, to form a mixed acetal. The use of the oxime hydrochloride avoids the addition of large amounts of pyridine salt, being able to use a catalytic ratio of pyridine salt with respect to the oxime hydrochloride in the order of 1:100 towards the 1:5 ratio disclosed in the examples of the patent document U.S. Pat. No. 4,990,602. It has also been observed that it is not necessary to use the pyridine hydrochloride disclosed in this document; in its place pyridine hydrobromide can be used, which is an equally efficient substitute, cheaper and more easily manipulated, as it is much less hygroscopic than the pyridine hydrochloride.
After the mixed acetal forming reaction and without its isolation being necessary, the silylation of the 2xe2x80x2 and 4xe2x80x3 position hydroxyls at low temperature is proceeded with, by means of the addition of a silylation reactive, giving rise to the erythromycin A 2xe2x80x2,4xe2x80x3-bis (trimethylsilyl)-9-[O-isopropoxy cyclohexyl] oxime. The reaction takes place in the same solvent used in the former stage: methylene chloride. The silylation reactive is obtained by a reaction between hexamethyldisilazane and imidazole in the presence of sulphuric acid, followed by the addition of chlortrimethylsilane.
In the following methylation reaction, dimethylsulfoxide, methyl iodide and potassium hydroxide are added to the erythromycin A 2xe2x80x2,4xe2x80x3-bis(trimethylsilyl)-9-[O-isopropoxycyclo-hexyl]oxime solution, which is not necessary to isolate either, to synthesize the erythromycin A 2xe2x80x2,4xe2x80x3-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxy cyclohexyl]oxime. To continue with the reactions sequence, the dimethylsulfoxide is extracted with water, the aforementioned intermediate remaining dissolved in methylene chloride. Next, a change of solvent is carried out, by means of distillation, leaving the intermediate erythromycin A 2xe2x80x2,4xe2x80x3-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclo-hexyl]oxime dissolved in methanol.
In the next stage the unprotection of the silyl groups and the acetal takes place, in a methanol/water solution and in the presence of formic acid, to obtain the clarithromycin 9-oxime, which precipitates at a basic pH and is recovered by filtration. Finally, this intermediate is dissolved in methanol and is treated with aqueous sodium metabisulphite at a pH of 4.5-5, adjusted with formic acid, to obtain clarithromycin, which is subsequently crystallized by means of adjustment to a basic pH.
The yield attained with this method is very high, being able to obtain a 70% yield from the oxime hydrochloride to the clarithromycin, which, if necessary, can be recrystallized by means of standard methods.
The starting material, i.e. erythromycin A 9-oxime hydrochloride can be obtained as is disclosed in the previous stage, explained further on, or rather following other methods disclosed in the bibliography, such as in the first part of example 3 of the patent U.S. Pat. No. 5,274,085.